TY - JOUR
T1 - The Intestinal Microbiome Restricts Alphavirus Infection and Dissemination through a Bile Acid-Type I IFN Signaling Axis
AU - Winkler, Emma S.
AU - Shrihari, Swathi
AU - Hykes, Barry L.
AU - Handley, Scott A.
AU - Andhey, Prabhakar S.
AU - Huang, Yan Jang S.
AU - Swain, Amanda
AU - Droit, Lindsay
AU - Chebrolu, Kranthi K.
AU - Mack, Matthias
AU - Vanlandingham, Dana L.
AU - Thackray, Larissa B.
AU - Cella, Marina
AU - Colonna, Marco
AU - Artyomov, Maxim N.
AU - Stappenbeck, Thaddeus S.
AU - Diamond, Michael S.
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/8/20
Y1 - 2020/8/20
N2 - Chikungunya virus (CHIKV), an emerging alphavirus, has infected millions of people. However, the factors modulating disease outcome remain poorly understood. Here, we show in germ-free mice or in oral antibiotic-treated conventionally housed mice with depleted intestinal microbiomes that greater CHIKV infection and spread occurs within 1 day of virus inoculation. Alteration of the microbiome alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single bacterial species, Clostridium scindens, or its derived metabolite, the secondary bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, symbiotic intestinal bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects viremia, dissemination, and potentially transmission.
AB - Chikungunya virus (CHIKV), an emerging alphavirus, has infected millions of people. However, the factors modulating disease outcome remain poorly understood. Here, we show in germ-free mice or in oral antibiotic-treated conventionally housed mice with depleted intestinal microbiomes that greater CHIKV infection and spread occurs within 1 day of virus inoculation. Alteration of the microbiome alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single bacterial species, Clostridium scindens, or its derived metabolite, the secondary bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, symbiotic intestinal bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects viremia, dissemination, and potentially transmission.
KW - Clostridium
KW - alphavirus
KW - bile acid
KW - chikungunya
KW - interferon
KW - microbiome
KW - monocyte
KW - pathogenesis
KW - plasmacytoid dendritic cell
UR - http://www.scopus.com/inward/record.url?scp=85088558339&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2020.06.029
DO - 10.1016/j.cell.2020.06.029
M3 - Article
C2 - 32668198
AN - SCOPUS:85088558339
SN - 0092-8674
VL - 182
SP - 901-918.e18
JO - Cell
JF - Cell
IS - 4
ER -